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Abstract

Purpose of review: The concentrations of several plasma amino acids increase in obesity. Notably, plasma total concentrations of the sulphur amino acid cysteine (tCys) are linearly associated with fat mass in large population studies. Animal and cellular experiments support the concept that cysteine may be obesogenic. Here we review experimental and epidemiologic findings linking cysteine and related compounds with fat regulation and obesity.

Recent findings: tCys, and to a lesser extent cystathionine, are the only plasma sulphur amino acids consistently associated with human obesity, whereas glutathione is inversely associated with BMI. Supplementing cyste(i)ne in rodents decreases energy expenditure and promotes adiposity, whereas defects of cysteine-synthesizing enzymes decrease body weight. In adipocytes, cysteine inhibits lipolysis and promotes lipogenesis via H2O2 production. Unlike most plasma amino acids, tCys levels do not decrease with gastric bypass-induced weight loss, further supporting the concept that elevated cysteine may be a cause, not a consequence of obesity. Although cysteine products (glutathione, taurine and H2S) are altered in obesity, they do not appear to explain cysteine's effects on body weight.

Summary: Cellular, animal and epidemiologic data are consistent with the view that cysteine is obesogenic. Targeted research linking in-vitro and in-vivo findings is needed to elucidate mechanisms involved.

INTRODUCTION

Methionine is the only essential sulphur amino acid (SAA). Upon activation to S-adenosylmethionine, methionine acts as a methyl donor, producing homocysteine, which can be remethylated to methionine. Alternatively, homocysteine is catabolized to cystathionine and subsequently cysteine by cystathionine beta-synthase (CBS) and cystathionase. CBS and cystathionase are under regulatory inhibition by insulin [1]. Cysteine can be used in formation of proteins, glutathione, or taurine (catalysed by cysteine dioxygenase). CBS and cystathionase also facilitate cysteine desulphurization, releasing hydrogen sulphide (H2S). Details of these processes, their regulation and biological significance were recently reviewed [2].

We recently highlighted the possibility that cysteine may be an unrecognized determinant of obesity [3]. Here we summarize cellular, animal and human data supporting this concept. For comparison, we also discuss in-vitro and in-vivo data linking related sulphur metabolites with fat regulation and body weight. For simplicity, methionine, cystathionine, homocysteine, cysteine and taurine, as well as the tripeptide glutathione will be referred to as ‘SAA’.

Cysteine is a thiol, which readily becomes oxidized, forming disulphide bonds with itself (cystine) or other thiols (mixed disulphide). Thus, plasma total cysteine (tCys) refers to all circulating forms including reduced cysteine (the thiol), cystine, and mixed disulphides. The latter include homocysteine-cysteine disulphide and albumin-bound cysteine. Nearly all nonprotein bound (free) cysteine in plasma is in oxidized (i.e. disulphide) state. Throughout this review, ‘cystine’ refers to the free disulphide, whereas ‘cysteine’ refers to the amino acid without specification of its form.

SULPHUR AMINO ACIDS AND HYDROGEN SULPHIDE IN RELATION TO OBESITY

Methionine

Newgard et al.[4] reported plasma amino acid concentrations in obesity. The only SAA investigated was methionine, which was identical in lean and obese individuals. We similarly found that plasma methionine was not associated with BMI [5], or with fat mass [6▪▪]. However, methionine intake was positively associated with BMI [7].

Homocysteine

There are conflicting reports on the associations of plasma total homocysteine (tHcy) with BMI. Variable correlations were found, including positive [8], negative [9] and no [10,11] associations. The discrepancy appears partly to relate to study design and statistical models employed. For example, we observed that a positive association of tHcy with BMI and fat mass changed to inverse when the model was adjusted for plasma tCys [6▪▪]. The conflicting results also suggest that association of tHcy with BMI is modest and subject to modification according to characteristics of the population under study. In weight loss trials, an increase of tHcy is frequently observed [12,13▪▪]. In high concentrations (100–500 μmol/l), homocysteine inhibits lipolysis in adipocytes [14].

Cystathionine

Fasting plasma cystathionine is modestly higher in overweight vs. lean individuals, and higher still in obese individuals [5]. We observed that this association is approximately linear across the BMI range, is explained by fat mass, and persists after adjustment for tCys [5,6▪▪]. In contrast to tCys, the relationship of cystathionine with BMI is attenuated by adjusting for serum lipids and apolipoproteins [5].

Cysteine

Several studies have reported a positive relationship of tCys with BMI, or elevation of tCys in overweight individuals [15–19]. Plasma cystine is also strongly associated with BMI (r = 0.49, P < 0.001, N = 47) [20▪]. However, cysteine is distinct from other amino acids that are elevated in plasma in obesity in several aspects, as discussed below. Experimental and epidemiologic evidence suggests that cysteine could be an unrecognized determinant of body weight.

Total cysteine and fat mass

Plasma tCys is associated with BMI almost exclusively via fat mass, as measured by dual energy X-ray absorptiometry (DXA) in approximately 5000 individuals [6▪▪]. From low to high tCys levels, there was a difference in fat mass of approximately 11 kg, after adjustment for lean mass. Waist circumference and waist-hip ratio also increased with increasing tCys (difference in waist circumference of 9 cm in women and 7 cm in men from lowest to highest quintile), suggesting a relation with visceral fat. The association of tCys with fat mass (partial r = 0.25, P < 0.001) remained robust after controlling for physical activity, energy intake, protein and fat consumption, and plasma/serum concentrations of other SAA, lipids, and creatinine [6▪▪]. These findings were replicated in 1550 individuals, in whom tCys was associated with a 3.5-fold risk of obesity after multiple adjustments [15].

Total cysteine and weight change

Changes in tCys and in BMI over 6 years were positively correlated [21]. Individuals whose plasma tCys increased from baseline to follow-up had a 2 kg higher fat mass at follow-up after controlling for baseline tCys and BMI [6▪▪]. Although it was not determined whether BMI/fat mass changes tracked tCys changes or vice versa, studies in obese patients undergoing gastric bypass show that tCys and cystine levels do not decrease despite major weight loss [13▪▪,22] (Fig. 1). A minor tCys reduction occurs after duodenal bypass surgery [13▪▪], likely due to malabsorption [23]. This suggests that fat mass is not a determinant of plasma tCys, in contrast to other amino acids that are elevated in obesity and drop after weight loss, including arginine [24], glutamate [4,13▪▪], leucine, isoleucine, valine and phenylalanine [4,22]. Table 1 summarizes changes in SAA and related compounds in obesity, and effect of weight loss following gastric bypass.

Genetic defects in cysteine-related enzymes and body weight

Mice defective in CBS or cystathionase, the enzymes involved in cysteine synthesis, are leaner than wild-type. Cystathionase knockout mice have slower weight gain and lower plasma cysteine, glutathione and H2S [43▪]. Of all organs, white adipose tissue mass is the most decreased (34% of wild-type). Supplementation with cysteine, but not with an H2S donor, restores plasma cysteine and weight gain, with the greatest increase reported in adipose tissue mass (53%). Food intake is not increased, suggesting an effect of cysteine on energy expenditure. Similarly in CBS knockout mice weight is reduced and is critically dependent on dietary cysteine content [44]. DXA analysis shows that the weight reduction is largely explained by lower fat mass (Kruger, personal communication). Spontaneously hypertensive rats with genetically reduced expression of folate transporter 1 (Folr1) have higher tCys concentrations, and exhibit adiposity and insulin resistance. In contrast, transgenic rats with increased expression of Folr1 show decreased cysteine levels and lower adiposity (Pravenec and Kožich, unpublished).

As recently reviewed [3], humans with genetic CBS deficiency have lower BMI, described as ‘tall and thin by the time they reach late childhood’. Down's syndrome (Trisomy 21) patients have an extra CBS allele, which is localized to chromosome 21. This results in high plasma tCys, and is associated with obesity. One genetic model with high tCys that conversely features lower body weight is the cysteine dioxygenase knockout mouse [45]. These mice have extremely low taurine levels and relatively modest cysteine elevation, with channelling of cysteine towards H2S formation. However, this model may be confounded by the severe taurine deficiency, which may reduce body mass as observed in the taurine-transporter knockout mouse [46].

Dietary cysteine intake and body weight

Limiting dietary cysteine is normally compensated by endogenous synthesis if methionine intake is sufficient. Thus, a diet restricted in both cysteine and methionine is needed to observe effects of cysteine deficiency. Such diets include the methionine-restricted diet which is devoid of cysteine and contains 0.17% methionine (25% of control), and the methionine-choline-deficient diet (MCD), a high-sucrose, high-fat diet devoid of methionine and choline. In rodents, these diets induce hypermetabolism, with decreased weight gain and body fat%, and resistance to diet-induced obesity [47–50]. A hallmark of methionine-restricted diets is suppression of hepatic stearoyl-coenzyme A desaturase-1 (SCD1) [48,49], a condition that promotes hyper-metabolism by inducing a shift from lipogenesis towards β-oxidation via hepatic adenosine monophosphate-activated protein kinase [51].

We postulated that effects of methionine-restriction are caused by cysteine deficiency, since plasma tCys is decreased in methionine-restricted rats [52,53], and tCys, but not methionine, is associated with human obesity [5,6▪▪]. Upon supplementing methionine-restricted rats with cysteine, effects of methionine-restriction on weight gain, serum lipids, adipokines and fatty acid profile were abrogated [54▪]. Crucially, tissue-specific effects of methionine-restriction on SCD1 expression and SCD1 activity indices were partly or completely reversed by cysteine, concomitant with a phenotype suggestive of decreased energy expenditure [54▪]. In a study in mice, a high cystine diet decreased energy expenditure, enhanced visceral adiposity and reduced glucose tolerance (Fig. 2) [55▪], with increased expression genes for lipogenic and diabetogenic enzymes. Some studies report that supplementation of N-acetylcysteine decreases fat mass [56,57]. As previously discussed [3], we postulate that N-acetylcysteine may have opposite effects on fat mass to those of cysteine due to possible contrast in the redox properties of the two compounds in vivo.

In rat adipocytes, cysteine inhibits catecholamine-stimulated lipolysis (Fig. 3), in concentrations ranging from 10 μmol/l to 1 mmol/l [37]. The lower end of this range is physiologically relevant, since reduced cysteine in human plasma is typically around 10 μmol/l [58]. Furthermore, cysteine enhances oxidation of glucose and its utilization in de-novo lipogenesis [38,42].

In line with in-vitro findings, plasma GSH is decreased in obesity [30], and the GSSG/GSH ratio is increased [29]. We observed a borderline inverse association of plasma total glutathione (tGSH) with BMI [5], and tGSH decreased with increasing waist circumference in metabolic syndrome patients [18]. Since intracellular glutathione is several orders of magnitude higher than plasma levels, it may be relevant to examine whole blood concentrations. We investigated the associations of blood-free (nonprotein-bound) glutathione (fGSH; which is largely intracellular and reduced) and blood-free cysteine (fCys; largely extracellular and oxidized) [76], with BMI in 877 individuals (cohort described in [77]). fCys was positively associated with BMI and fGSH [3]. However, within the higher fCys categories, high fGSH was associated with lower BMI. Thus, BMI was highest in individuals with greatest fCys and lowest fGSH (Fig. 4).

Taurine

In contrast to cysteine, taurine inhibits insulin-stimulated H2O2 release and activates lipolysis in adipocytes [31], in line with earlier reports that taurine supplementation decreased weight gain and adiposity in mice [78]. However, in humans, taurine supplements failed to decrease BMI [79,80], despite modest weight reduction in one study [80]. Plasma taurine was not associated with BMI in a general population sample [5] and was unchanged in type 2 diabetes [27]. Yet in severely obese individuals, plasma taurine was clearly higher than in normal weight controls [13▪▪]. This may reflect enhanced oxidation of cysteine to taurine in obesity via cysteine dioxygenase, which is induced in adipose tissue by cysteine excess [81]. In rats, urine taurine is higher in obesity induced by a high fat diet [82]. Conflictingly, high urine taurine levels were strongly associated with low BMI in a large study [32]. However, urine taurine is a good marker of type of diet [83] including fish intake, which may independently influence BMI. Overall, the epidemiologic association of taurine with obesity needs to be reassessed using better markers of body taurine status, such as whole blood taurine, which is several folds higher than plasma levels and less subject to dietary fluctuations [84].

Hydrogen sulphide

A potential role for H2S in metabolic regulation was recently reviewed [85,86]. When administered in sub-toxic doses H2S can induce a hypometabolic state in some mammals [87]. However, evidence suggests that endogenous H2S is not the mediator of cysteine-induced weight gain, since an H2S donor did not rescue weight gain in cystathionase knockout mice [43▪]. Plasma H2S concentrations are decreased in human obesity and correlate inversely with BMI and waist-hip ratio [34]. This may seem unusual in view of the tCys elevation in obesity, but an inverse correlation between plasma tCys and H2S has previously been reported [88]. Also in type 1 diabetic rodent models, plasma H2S is decreased [89,90] despite induction of its tissue synthesizing enzymes [89,90]. Thus plasma H2S does not appear to correlate with tCys or to reflect hepatic synthesis. It was recently shown that CBS and cystathionase enzymes circulate in plasma and produce H2S in human blood [91▪,92], which may contribute to plasma H2S.

CONCLUSION

Cysteine is hitherto the only amino acid for which available cellular, animal and epidemiologic data all point to an obesogenic action. Although branched chain amino acids are consistently elevated in human obesity [4], effects of transgenic [93] and nutritional [4,94] manipulation of these amino acids in animals are in opposite direction to human findings. tCys is also distinct in that it does not markedly drop with major weight loss after bariatric surgery, suggesting that tCys elevation is not a consequence of increased body fat. Studies in rodents fed diets with low methionine/cysteine or excess cysteine suggest that cysteine may promote obesity by decreasing energy expenditure via an influence on SCD1. Cysteine also inhibits lipolysis and promotes lipogenesis in adipocytes via H2O2 production. In vitro, H2O2 stimulates enzymes and pathways that favour lipid storage, including hormone-sensitive lipase, PTP-1b, and mTORC1. In light of these observations, the positive association of plasma cystine, H2O2, ceruloplasmin and GSSG/GSH ratio with human obesity suggest that a shift of thiol redox state towards oxidation may favour fat storage, in addition to driving metabolic complications of obesity [62]. However, direct evidence linking elevated plasma tCys in humans with SCD1 function, energy expenditure or H2O2 signalling pathways has yet to be demonstrated.

Acknowledgements

Conflicts of interest

The study was supported by the Norwegian Research Council and the Charles Wolfson Charitable Trust, and by grants from the Ministry of Health of the Czech Republic (No. NS10036-4) and Ministry of Education of the Czech Republic (No. MSM0021620806).

The first study demonstrating that the tCys-BMI association is mediated by fat mass. Shows a quantitatively large difference in fat mass (11 kg) from low to high tCys levels in more than 5000 subjects.

Describes 1-year changes in plasma sulphur amino acids and glutamate, as well as the related enzyme gamma glutamyl-transferrase in 60 patients undergoing bariatric surgery. The drop in glutamate, methionine and cystathionine as well as in gamma glutamyl-transferase activity contrasts with the relative stability of cysteine with weight loss.

Shows decreased body weight, maximally affecting adipose tissue mass, and decreased plasma cysteine in cystathionase-deficient mice. Both conditions are reversed by supplementation of cysteine, but not of a hydrogen sulphide donor.

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